ClinGen Dosage Sensitivity Curation Page

CHRNA7

  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

CHRNA7 is overlapped by the recurrent 15q13.3 (BP4-BP5) and nested 15q13.3 (D-CHRNA7 to BP5) deletion intervals. The distal (3 prime) portion of this gene is overlapped by a segmental duplication, which confounds detection of deletions in this region. Thus far, focal alterations (deletions or loss-of-function mutations) affecting CHRNA7 have not been reported. Therefore the haploinsufficiency score is 0. Past studies have attributed the clinical phenotype observed in individuals with deletions involving the 15q13.3 (BP4-BP5) and (D-CHRNA7 to BP5) regions to the CHRNA7 gene. However the longer isoform of OTUD7A was not previously described and is now known to be included in the previously reported deletions involving CHRNA7. Currently there is insufficient evidence to demonstrate pathogenicity of CHRNA7 deletion. Please see the linked regions for further evidence relating to the 15q13.3 (BP4-BP5) and 15q13.3 (D-CHRNA7 to BP5) recurrent deletion/duplication. Additional literature is summarized below: Case-control studies PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, deletions of CHRNA7 were observed in 83/29,085 cases versus 84/19,584 controls (p= 0.997, LR=0.665 (0.504 to 0.878)), demonstrating a lack of enrichment in the clinical population. Case reports PMID: 26275793 Westerfield et al. (2015) retrospectively analyzed WES data from 19,218 patients and identified one patient (patient 26, table 2) with a splice variant (c.241-1G>A) in the CHRNA7 gene. The functional effect of this variant was not studied. Patient 26 had clinical features including intellectual disability and developmental delay, seizures, and hypotonia. This variant was inherited from a father with mild learning delay and no seizures or other health concerns were noted.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

CHRNA7 is overlapped by the recurrent 15q13.3 (BP4-BP5) and nested 15q13.3 (D-CHRNA7 to BP5) duplication intervals. Assessment of the clinical significance of CHRNA7 duplications is confounded by the presence of a distal (3 prime) overlapping segmental duplication overlapping this gene, resulting in the inability to distinguish between duplications encompassing CHRNA7 (focal duplications) and partial gene duplications, which may disrupt gene expression. As it is uncertain whether reported duplications involving CHRNA7 are focal, the triplosensitivity score is 0. Past studies have attributed the clinical phenotype observed in individuals with duplications involving the 15q13.3 (BP4-BP5) and (D-CHRNA7 to BP5) regions to the CHRNA7 gene. However the longer isoform of OTUD7A was not previously described and is now known to be included in the previously reported duplications involving CHRNA7. Currently there is insufficient evidence to demonstrate pathogenicity of CHRNA7 duplication (whole gene or partial). Please see the linked regions for further evidence relating to the 15q13.3 (BP4-BP5) and 15q13.3 (D-CHRNA7 to BP5) recurrent deletion/duplication. Additional literature is summarized below: PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, duplications (uncertain if whole gene or partial) of CHRNA7 were observed in 202/29,085 cases versus 147/19,584 controls (p= 0.780, LR=0.925 (0.764 to 1.12)), demonstrating a lack of enrichment in the clinical population.